Substitution of both chloro and sulfinyl groups of aryl 1-chlorocyclopropyl sulfoxides in one-pot via cyclopropylmagnesium carbenoids: a synthesis of multi-substituted cyclopropanes

Article abstract of DOI:10.1016/j.tetlet.2009.06.019

The rearrangement of cyclopropylmagnesium carbenoids, which were generated from aryl 1-chlorocyclopropyl sulfoxides with a Grignard reagent, to allenes was found to be suppressed by adding HMPA as an additive. Alkylation of the cyclopropylmagnesium carben

Full text of DOI:10.1016/j.tetlet.2009.06.019

Tetrahedron Letters 50 (2009) 4754–4758
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Substitution of both chloro and sulfinyl groups of aryl 1-chlorocyclopropyl
sulfoxides in one-pot via cyclopropylmagnesium carbenoids: a synthesis of
multi-substituted cyclopropanes
*
Masanobu Yajima, Ryo Nonaka, Hironori Yamashita, Tsuyoshi Satoh
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-funagawara-machi 12, Shinjuku-ku, Tokyo 162-0826, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The rearrangement of cyclopropylmagnesium carbenoids, which were generated from aryl 1-chlorocyclo-
propyl sulfoxides with a Grignard reagent, to allenes was found to be suppressed by adding HMPA as an
additive. Alkylation of the cyclopropylmagnesium carbenoids with the Grignard reagent gives mainly
alkylated cyclopropylmagnesium chloride instead. The cyclopropylmagnesium chloride intermediate
can be trapped with several electrophiles to afford multi-substituted cyclopropanes. This procedure pro-
vides a new method for a synthesis of multi-substituted cyclopropanes.
Received 18 May 2009
Revised 3 June 2009
Accepted 5 June 2009
Available online 9 June 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Magnesium carbenoid
Cyclopropylmagnesium carbenoid
Cyclopropane
One-pot synthesis
Doering–LaFlamme allene synthesis
1. Introduction
This intermediate 4 was proved to be reactive with several electro-
philes to give multi-substituted cyclopropanes 5. This is a new
The synthesis of allenes from gem-dihalocyclopropanes, which are
derived from olefins with dihalocarbenes, is known as Doering–LaFl-
ammeallenesynthesis1 (or Doering–Moore–Skattebol reaction2). The
key reaction of this procedure is the cyclopropylidene-allene rear-
rangement (Doering–LaFlamme-type rearrangement) of the cyclo-
propylidenes generated from the gem-dihalocyclopropanes3 with
alkyllithiums or Grignard reagents.4
one-pot synthesis of multi-substituted cyclopropanes from easily
available aryl 1-chlorocyclopropyl sulfoxides 1. Details of this pro-
cedure are described.
2. Results and discussion
At first, 1-chlorocyclopropyl p-tolyl sulfoxide 6 was synthesized
as the representative starting material in this study from tert-butyl
acrylate and chloromethyl p-tolyl sulfoxide based on the procedure
reported by Toyota.8 As the study for obtaining an allene as the de-
sired product,7 sulfoxide 6 was treated with 2 equivalents of i-
PrMgCl in toluene at 50 °C for 1 min (Table 1, entry 1). This reac-
tion gave allene 7 in 74% as the desired product with isopropylated
cyclopropane 8 as a byproduct. Lowering the reaction temperature
to 0 °C did not give better result (entry 2).
We are also interested in the reaction of cyclopropylidene carb-
enoids, especially cyclopropylmagnesium carbenoids 2 generated
from aryl 1-chlorocyclopropyl sulfoxides 1 by the sulfoxide-mag-
nesium exchange reaction (Scheme 1). Thus, sulfoxides 1 were syn-
thesized from olefins5 or
a
,b-unsaturated carbonyl compounds.6
Treatment of 1 with PhMgCl5 or alkylmagnesium chloride7 in
THF or toluene at 0 °C resulted in the formation of cyclopropylmag-
nesium carbenoids 2. Doering–LaFlamme-type rearrangement
then took place to afford allenes 3 in good yields.5,7
In order to know the effect of additives in this reaction, HMPA
was added to the reaction mixture and we observed dramatic
change in the reaction (entry 3). Thus, treatment of 6 in toluene
with two equivalents of i-PrMgCl in the presence of 8 equiv of
HMPA at 0 °C for 30 min afforded chlorocyclopropane 9 as the
product in 88% yield. No allene 7 and isopropylated cyclopropane
8 were observed. When this reaction was quenched with CH3OD,
cyclopropane deuterated at the carbon bearing the chlorine atom
9 with 86% deuterium content was obtained. This result indicated
that the intermediate, cyclopropylmagnesium carbenoid 10 (see
During the course of our above-mentioned investigation, we re-
cently found that addition of hexamethylphosphoramide (HMPA)
as an additive in the reaction mixture suppressed the cyclopropy-
lidene-allene rearrangement. Alkylation of the cyclopropylmagne-
sium carbenoid 2 with the used Grignard reagent was preferred
instead to give alkylated cyclopropylmagnesium intermediate 4.
* Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261 4631.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.019

M. Yajima et al. / Tetrahedron Letters 50 (2009) 4754–4758
4755
R2 R1
R2 R1
Doering-LaFlamme-type
rearrangement
R1
R2
RMgX
H
R3
Cl
R3
Cl
.
R3
SAr
MgX
Lit. 5, 7
3
1
2
O
R2 R1
R2 R1
RMgX
Electrophile
R3
R3
E
MgX
R
R
in the presence
of HMPA
5
4
Scheme 1.
Table 1
Treatment of 1-chlorocyclopropyl p-tolyl sulfoxide 6 with i-PrMgCl without and with HMPA
H
CH2OTr
H
CH2OTr
H
CH2OTr
H (D)
i-PrMgCl
Toluene
H
H
CH2OTr
H
.
Cl
+
+
Cl
S(O)Tol
H (D)
9
7
6
8
Entry
i-PrMgCl (equiv)
Conditions
MMPA
7/Yield (%)
8/Yield (%)
9/Yield (%)
1
2
3
4
2
2
2
8
50 °C, 1 min
0 °C, 30 min
0 °C, 30 min
0 °C, 30 min
Non
Non
8 equiv
8 equiv
74
65
0
15
27
0
0
0
88a
Trace
Trace
85b
a
When this reaction was quenched with CH3OD, deuterated cyclopropane 9 (86% deuterium content) was obtained. About 5% of trans-isomer was present as the product.
When this reaction was quenched with CH3OD, deuterated cyclopropane 8 (99% deuterium content) was obtained. About 9% of cis-isomer was present as the product.
b
Scheme 2), is stable at 0 °C for at least 30 min. This was very inter-
stabilized by the coordination of HMPA with the magnesium and
the rearrangement to allene must be prevented. When this reac-
tion was conducted with slight excess of i-PrMgCl, quenching this
reaction with water gives cis-1-chloro-2-trityloxymethylcyclopro-
pane 9 (Table 1, entry 3). On the other hand, when this reaction
was conducted with large excess of i-PrMgCl, intermediate 10 is at-
tacked by i-PrMgCl with inversion of the carbenoid carbon10 (or via
a magnesium ate complex) to give isopropylated cyclopropylmag-
nesium chloride 11. Quenching of this intermediate with water
gives trans-1-isopropyl-2-trityloxymethylcyclopropane 8 (Table 1,
entry 4).
esting result for us because we had presumed that cyclopropyl-
magnesium carbenoids were unstable above À60 °C to produce
allenes.5
Further interesting result was obtained when the reaction was
conducted with excess of i-PrMgCl (entry 4). Thus, treatment of 6
with 8 equiv of i-PrMgCl in the presence of 8 equiv of HMPA at
0 °C for 30 min gave isopropylated cyclopropane 8 in 85% yield
with trace of 7 and 9. When this reaction was quenched with
CH3OD, cyclopropane deuterated at the carbon bearing the isopro-
pyl group 8 with 99% deuterium content was obtained.
Based on the results mentioned above, the progress and the
mechanism of these reactions can be estimated as follows (Scheme
2). At first, the sulfoxide-magnesium exchange reaction of 6 takes
place with i-PrMgCl with retention of the stereochemistry of the
carbon bearing the sulfinyl group9 to afford cyclopropylmagne-
sium carbenoid intermediate 10. This carbenoid is thought to be
As we were aware that this procedure must become good way
for a synthesis of multi-substituted cyclopropanes, the reaction
of several electrophiles with the isopropylated cyclopropylmagne-
sium chloride intermediate 11 was investigated and the results are
summarized in Table 2. Thus, sulfoxide 6 was treated with 8 equiv
of i-PrMgCl in toluene at 0 °C in the presence of HMPA (8 equiv) for
H
CH2OTr
H
CH2OTr
H (D)
H
CH2OTr
H2O or
CH3OD
H
CH2OTr
MgCl
inversion of the
carbenoid carbon
i-PrMgCl
Cl
Cl
CH3
MgCl
S(O)Tol
H3C
11
MgCl
6
10
8
O
H2O or
CH3OD
H
CH2OTr
P(NMe2)3
Cl
H (D)
9
Scheme 2.

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M. Yajima et al. / Tetrahedron Letters 50 (2009) 4754–4758
Table 2
Treatment of 1-chlorocyclopropyl p-tolyl sulfoxide 6 with i-PrMgCl in the presence of HMPA followed by electrophiles
H
CH2OTr
H
CH2OTr
MgCl
H
CH2OTr
E
Electrophile
(10 eq)
i-PrMgCl
(8 eq)
Cl
HMPA (8 eq)
Toluene
Additive
S(O)Tol
0 °C, 1 h
6
0 °C, 30 min
11
12
Entry
Electrophile
Additive
12/Yield (%)
Ratio of diastereomersa
1
2
3
4
5
6
7
CH3I
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
Al(CH3)2Cl (2 equiv)
Al(CH3)2Cl (2 equiv)
Al(CH3)2Cl (2 equiv)
84
83
76
65
76
20:1
10:1
10:1
20:1
1:1b
CH2@CHCH2I
PhCH2Br
PhCOCl
PhCHO
CH3COCH3
PhCOPh
c
—
c
—
The ratio of two diastereomers was determined from their 1H NMR.
The product was obtained as a 1:1 mixture of two diastereomers with respect to the carbon bearing the hydroxyl group.
Compound 8 was obtained as the main product.
a
b
c
30 min. To this reaction mixture, copper(I) iodide (CuI; 10 mol %)
followed by iodomethane (10 equiv) was added and the reaction
mixture was stirred at 0 °C for 1 h (Table 2, entry 1). Fortunately,
the desired methylated product 12 (E = CH3) was obtained in 84%
yield. The product was proved to be a mixture of two isomers
(the ratio 20:1) and structure of the main product was confirmed
as shown in Table 2 by NOESY spectrum (NOE was observed be-
tween the hydrogen of the introduced methyl group and the
hydrogen on the carbon bearing the trityloxy group). It is notewor-
thy that no methylation was observed when this reaction was con-
ducted without CuI.
Allyl iodide and benzyl bromide reacted well with 11 to give the
desired tri-substituted cyclopropanes in 83 and 76% yield, respec-
tively (entries 2 and 3). Benzoyl chloride also reacted with 11 in
the presence of CuI to afford a cyclopropane bearing benzoyl sub-
stituent (entry 4).11 The reaction with benzaldehyde without an
additive gave only complex mixture; however, it was found that
dimethylaluminum chloride worked well as a Lewis acid to give
the desired adduct in 76% yield (entry 5). We tried the reaction
with acetone and benzophenone without or with dimethylalumi-
num chloride; however, no adduct was obtained. In these cases,
isopropylated cyclopropane 8 was obtained as the main product.
In order to investigate the generality of this reaction, three aryl
1-chlorocyclopropyl sulfoxides (13a,12 13b,6 and 13c6) were syn-
thesized and these sulfoxides were treated with i-PrMgCl followed
by electrophiles. The results are summarized in Table 3. When 1-
chlorocyclopropyl phenyl sulfoxide with no substituent on the
cyclopropane ring 13a was used in this reaction, gem-disubstituted
cyclopropanes 14 were obtained in up to 77% yield (entries 1–3).
The alkylation, benzoylation, and addition to benzaldehyde pro-
ceed smoothly in the presence of CuI or dimethylaluminum
chloride.
When this reaction was carried out with 1-chlorocyclopropyl
p-tolyl sulfoxide having two substituents at 2-position on the
cyclopropane ring 13b, the expected isopropylated product 14
was obtained in 66% yield; however, significant amount of allene
Table 3
Treatment of 1-chlorocyclopropyl aryl sulfoxides 13 with i-PrMgCl in the presence of HMPA followed by electrophiles
R1
R2
R1
R2
Electrophile
(10 eq)
i-PrMgCl
(8 eq)
H
R1
R2
.
Cl
S(O)Ar
+
E
R3
HMPA (8 eq)
Toluene
Additive
R3
R3
0 °C, 1 h
15
0 °C, 30 min
14
13a R1=R2=R3=H, Ar=Ph
b R1=CH3, R2=CH2OTr, R3=H, Ar=Tol
c R1=CH3, R2=CH2OTr , R3=CH3, Ar=Tol
Entry
R1
H
R2
R3
H
Ar
Ph
Electrophile
Additive
14/Yield (%)
Ratio of diastereomersa
15/Yield (%)
1
2
3
4
5
6
7
8
13a
13b
H
PhCH2CH2I
PhCOCl
PhCHO
H3O+
CuI (10 mol %)
CuI (10 mol %)
Al(CH3)2Cl (2 equiv)
68
77
70
66
58
64
59
15
Single isomer
10:3
5:2
10:3
5:1
CH3
CH2OTr
H
Tol
23
23
25
21
77
CH3I
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CH2@CHCH2I
PhCOCl
H3O+
13c
CH3
CH2OTr
CH3
Tol
Single isomer
a
The ratio of two diastereomers was determined from their 1H NMR.

M. Yajima et al. / Tetrahedron Letters 50 (2009) 4754–4758
4757
15 (23%) was also observed (entry 4). This result indicated that
the corresponding highly substituted cyclopropylmagnesium
carbenoid was prone to rearrange to allene. Although the cyclo-
propylmagnesium carbenoid has this nature, tetra-substituted
cyclopropanes 14 were synthesized in up to 64% yield (entries
5–7). It is noteworthy that the produced cyclopropanes 14 have
two quaternary carbons.
Finally, tri-substituted cyclopropylmagnesium carbenoid was
generated from 13c (entry 8). In this case, it was found that the de-
sired isopropylated product was obtained in only 15% yield and the
yield of allene 15 was 77%. This result indicates that the substitu-
ents on the cyclopropylmagnesium carbenoid retard the alkylation,
perhaps by steric hindrance, and also promote the Doering–LaFl-
amme-type rearrangement.
The reaction of 6 with phenylmagnesium chloride was found to
be troublesome (entry 15). Phenylation of the cyclopropylmagne-
sium carbenoid intermediate was found to be slow in the reaction
of 6 with phenylmagnesium chloride under the conditions which
smoothly gave cyclopropylmagnesium carbenoid 10; and allene 7
was produced in 25% yield. We concluded that phenylmagnesium
halides were not suitable in this procedure. In entries 16–25 the
reactions of 13b and 13c with ethylmagnesium chloride and cyclo-
pentylmagnesium chloride followed by electrophiles are summa-
rized. As shown, the results are quite similar with those of the
reactions of 13b and 13c with i-PrMgCl shown in Table 3, entries
4–8.
In conclusion, we have found that HMPA suppresses the cyclo-
propylidene-allene rearrangement. Base on this finding, we estab-
Finally, investigation of this reaction with ethylmagnesium
chloride, cyclopentylmagnesium chloride, and phenylmagnesium
chloride was carried out using aryl 1-chlorocyclopropyl sulfoxides
6 and 13a–c as the substrates and the results are summarized in
Table 4. Ethylmagnesium chloride and cyclopentyl magnesium
chloride reacted with 13a to afford the alkylated cyclopropylmag-
nesium intermediates, which could be trapped with iodoalkane,
benzoyl chloride, and benzaldehyde to afford gem-disubstituted
cyclopropanes in up to 73% yield (entries 1–6). This procedure also
worked well with 1-chlorocyclopropyl p-tolyl sulfoxide 6 (entries
7–14).
lished a procedure for the synthesis of multi-substituted
cyclopropanes from aryl 1-chlorocyclopropyl sulfoxides in one-
pot via the formation and alkylation of cyclopropylmagnesium
carbenoids as the key reactions. This is the first example for the
double substitution of chlorine and sulfinyl groups on a cyclopro-
pane ring via cyclopropylmagnesium carbenoid intermediate.13
Cyclopropanes are unambiguously one of the most important and
fundamental compounds in organic and synthetic organic chemis-
tries.14 The results presented herein will contribute greatly to the
synthesis of multi-substituted cyclopropanes and to the chemistry
of magnesium carbenoids.
Table 4
Treatment of 1-chlorocyclopropyl aryl sulfoxides 13 with Grignard reagent in the presence of HMPA followed by electrophiles
R1
R2
R1
R2
Electrophile
(10 eq)
RMgCl
(8 eq)
H
R1
R2
.
Cl
S(O)Ar
+
E
HMPA (8 eq)
Toluene
0 °C, 30 min
R3
Additive
0 °C, 1 h
R3
R3
R
7 or 15
16
6 R1=CH2OTr , R2=R3=H, Ar=Tol
13a R1=R2=R3=H, Ar=Ph
b R1=CH3, R2=CH2OTr, R3=H, Ar=Tol
c R1=CH3, R2=CH2OTr, R3=CH3, Ar=Tol
Entry
R1
H
R2
H
R3
H
Ar
Ph
R
Electrophile
Additivea
16/Yield (%)
Ratio of diastereomersa
7 or 15/Yield (%)
1
2
3
4
5
6
CH3CH2
PhCH2CH2I
PhCOCl
PhCHO
PhCH2CH2I
PhCOCl
PhCHO
CuI
CuI
Al(CH3)2Cl
CuI
CuI
57
59
54
60
67
73
Single isomer
Single isomer
Al(CH3)2Cl
7
8
9
CH2OTr
H
H
Tol
CH3CH2
H3O+
CH3I
CH2@CHCH2I
PhCOCl
H3O+
74
61
68
60
73
62
62
58
38
61
53
49
55
64
58
45
50
10
13
10:1
5:1
5:1
5:1
10:1
7:1
10:1
20:1
Single isomer
5:1
10:3
10:3
4:1
5:1
5:2
5:1
CuI
CuI
CuI
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CH3I
CuI
CuI
CuI
CH2@CHCH2I
PhCOCl
H3O+
Ph
CH3CH2
25
31
34
34
32
29
25
30
25
84
76
CH3
CH2OTr
H
Tol
Tol
H3O+
CH3I
CuI
CuI
CuI
CH2@CHCH2I
PhCOCl
H3O+
CH3I
CuI
CuI
CuI
CH2@CHCH2I
PhCOCl
H3O+
7:1
CH3
CH2OTr
CH3
CH3CH2
Single isomer
Single isomer
H3O+
a
Ten mol % of CuI or 2 equiv of Al(CH3)2Cl was used as the additive.

4758
M. Yajima et al. / Tetrahedron Letters 50 (2009) 4754–4758
(a) Hoffmann, R. W.; Holzer, B.; Knopff, O.; Harms, K. Angew. Chem., Int. Ed.
Acknowledgments
2000, 39, 3072; (b) Hoffmann, R. W. Chem. Soc. Rev. 2003, 32, 225.
11. A synthesis of 12 (E = PhCO; Table 2, entry 4) is reported as a representative
example of this procedure. To a flame-dried flask, 0.5 ml of toluene, i-PrMgCl
(2.0 M solution in diethyl ether; 0.4 ml, 0.8 mmol), and HMPA (0.14 ml;
0.8 mmol) were successively added at 0 °C under argon atmosphere. After
stirring for 10 min, a solution of cyclopropyl sulfoxide 6 (49 mg; 0.1 mmol) in
0.5 ml of toluene was added to the mixture dropwise with stirring and the
whole mixture was stirred at 0 °C for 30 min. To the reaction mixture were
successively added copper (I) iodide (2 mg; 0.01 mmol) and benzoyl chloride
(0.132 ml; 1 mmol) and the reaction mixture was stirred at 0 °C for 1 h. The
reaction was quenched by adding satd aq NH4Cl. The whole was extracted
three times with CHCl3. The organic layer was dried over MgSO4 and
concentrated in vacuo. The product was purified by flash column
chromatography (hexane/AcOEt) to give 12 (E = PhCO) (30 mg; 65%) as
colorless crystals. Main product; mp 133–133.5 °C (Et2O–hexane), IR (KBr);
This work was supported by a Grant-in-Aid for Scientific Re-
search No. 19590018 from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, and TUS Grant for Research
Promotion from Tokyo University of Science, which are gratefully
acknowledged.
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